In case control and prospective studies, sensitization to one or more of the major indoor allergens, i.e. mite, cat, dog or cockroach, has been the most consistent risk factor for asthma. Furthermore, in most of these studies, the prevalence of sensitization to mite or cockroach was directly related to increasing allergen exposure. By contrast, in several different studies, the presence of a cat in the home or high exposure to cat allergen has been associated with a decreased risk of sensitization and asthma. A partial explanation of this phenomenon comes from the finding that many of the children exposed to high concentrations of cat allergen [i.e. z20, ug Fel d 1/g dust] have made IgG and IgG4 Abs to Fel d I without IgE Ab or skin sensitization. Since expression of the gene for IgG4 is dependent on the Th2 cytokine IL-4, this IgG/IgG4 Ab response should be regarded as a modified Th2 response. Preliminary evidence suggests that this response is not related to asthma. The significance of the modified (or tolerant) Th2 response will be investigated by monitoring specific Abs to Fel d 1 of different isotypes and Abs to other allergens in sera from children enrolled in 3 prospective studies: a study on approximately 2000 school age children in Sweden, many of whom have high exposure to cat or dog allergens; a birth cohort in Boston; and a birth cohort in New Hampshire. The objectives are to confirm the prevalence of this form of high dose tolerance; to answer whether it has any relationship to asthma or other allergic symptoms; to investigate whether any other allergens can induce this response and whether the presence of an IgG/IgG4 Ab response to Fel d 1 influences the response to other allergens. Skin testing and nasal challenge will be used to identify whether subjects with IgG/IgG4 Ab to Fel d I make any local response, either immediate or delayed to cat allergens. The immunologic mechanisms controlling the tolerant response will be investigated by studying circulating T cells in vitro, using whole antigen (Fel d 1) and peptides. These studies will focus on the specificity of the T cell response in subjects with different immune responses to cat allergen, characterization of Fel d l-specific T cells, and the effects of antigen dose on T cell phenotype and Fel d l-specific Ab isotype production. The results will provide insight into the factors that control the prevalence of allergic disease. In addition, the studies will provide further understanding of those aspects of the response to allergens that put patients at risk for both symptomatic asthma and acute exacerbations of asthma.